Patent ES-8400749-A1 (ES)
Title: Mfg. antibacterial 2,3-di:substd.-2-penem derivs. and analogues
IPC: C07D499/00
Filed: 1982-05-12
Abstract: EP--58317 A Prepn. of 2,3-disubstd.-2-penem derivs. and analogues of formula (I) and their salts comprises treating a beta-lactam cpd. of formula (II) with a trivalent organophosphorus cpd. (III). - R1 is H, 1-6C alkyl, acylamino, R4-CH(OR5) or R4-CHR8; R4 is H, 1-6C alkyl, aryl or heteroaryl; R5 is Hor a hydroxy-protecting gp.; R8 is halogen, SR9 or NR10R11; R9 is 1-6C alkyl, H or an S-protecting gp.; one of R10 and R11 is an N-protecting gp. and the other is H, 1-6C alkyl, aryl, aralkyl, or acyl; or R10 and R11 are H, 1-6C alkyl, aryl, aralkyl, or acyl, provided that when one is H, then the other is acyl; R2 is e.g. 1-6C alkyl; R3 is CN, tetrazolyl or COOR6; R6 is H, trihalomethyl alkyl, 1-6C alkyl, an allylic gp., a metabolisable ester gp. or a carboxy-protecting gp.; X and Z are S, O or NR7; R7 is H, acyl, 1-6C alkyl, aryl, an N-protecting gp., -CH2- or -(CH2)2-. In cpds. (II) (1) R5 is a hydroxy-protecting gp.; (2) R9 is 1-6C alkyl or an S-protecting gp.; (3) R7 is not H; (4) any COOH gps. in R2 is esterified and (5) R6 is not H). - Cpds. (I) are broad-spectrum antibacterial agents and intermediats; some cpds. (I; X is S and Z is S or (CH2)2) are described in EP--13662 and ---3960. Dose is 5-200 mg/kg daily. Some cpds. (I) are new. EPAB- EP--58317 B Prepn. of 2,3-disubstd.-2-penem derivs. and analogues of formula (I) and their salts comprises treating a beta-lactam cpd. of formula (II) with a trivalent organophosphorus cpd. (III). - R1 is H, 1-6C alkyl, acylamino, R4-CH(OR5) or R4-CHR8; R4 is H, 1-6C alkyl, aryl or heteroaryl; R5 is Hor a hydroxy-protecting gp.; R8 is halogen, SR9 or NR10R11; R9 is 1-6C alkyl, H or an S-protecting gp.; one of R10 and R11 is an N-protecting gp. and the other is H, 1-6C alkyl, aryl, aralkyl, or acyl; or R10 and R11 are H, 1-6C alkyl, aryl, aralkyl, or acyl, provided that when one is H, then the other is acyl; R2 is e.g. 1-6C alkyl; R3 is CN, tetrazolyl or COOR6; R6 is H, trihalomethyl alkyl, 1-6C alkyl, an allylic gp., a metabolisable ester gp. or a carboxy-protecting gp.; X and Z are S, O or NR7; R7 is H, acyl, 1-6C alkyl, aryl, an N-protecting gp., -CH2- or -(CH2)2-. In cpds. (II) (1) R5 is a hydroxy-protecting gp.; (2) R9 is 1-6C alkyl or an S-protecting gp.; (3) R7 is not H; (4) any COOH gps. in R2 is esterified and (5) R6 is not H). - Cpds. (I) are broad-spectrum antibacterial agents and intermediats; some cpds. (I; X is S and Z is S or (CH2)2) are described in EP--13662 and ---3960. Dose is 5-200 mg/kg daily. Some cpds. (I) are new.  (74pp) - EP--58317 B A process for the preparation of a compound of the following general formula (I) in which R1 is hydrogen, C1-C6 alkyl, acylamino or R4-CH(OR5)- wherein R4 is hydrogen, C1-C6 alkyl, aryl, phenyl substituted by C1-C6 alkyl, by C1-C6 alkoxy or by halogen, or heteroaryl, said heteroaryl being an aryl group having a heteroatom in the ring and optionally having 1 to 3 C1-C6 alkyl substitutents, and R5 is hydrogen or an hydroxy protecting group; R2 is C1-C6 alkyl, aryl, phenyl substituted by C1-C6 alkyl, by C1-C6 alkoxy or by halogen, C1-C6 alkyl substituted by one or more aryl group, aminoalkyl, N-protected aminoalkyl, hydroxyalkyl, O-protected hydroxyalkyl, an optionally esterified, optionally N-protected alpha-amino acid residue or an optionally esterfied carboxylyl group; R3 is nitrile, tetrazolyl or -COOR6, wherein R6 is yrogen, -Alk-C(Hal)3 (in which Hal is halogen and Alk represents a C1-C6 alkylene radical), C1-C6 alkyl, aryl, phenyl substituted by C1-C6 alkyl, by C1-C6 alkoxy or by halogen, an allylic group, an ester group which can be metabolically removed in vivo, or a carboxy protecting group; X and Z are independently sulphur, oxygen, -CH2-, -CH2-CH2, or the radical=NR7 in which R7 is hydrogen, carboxylic acid acyl, C1-C6 alkyl, cyclolyl containing 3 to 6 carbon atoms, aryl, phenyl ssubstitutedd by C1-C6 alkyl, by C1-C6 alkoxy or by halogen, or an N-protecting group; or a pharmaceutically acceptable salt thereof; characterised by reacting an appropriate compound of the following general formula (II) in which R1, R2, R3 and X and Z are as defined above wherein R5 is a hydroxy protecting group, R7 is not hydrogen, any carboxy group in substituent R2 is esterified, and R6 is not hydrogen; with an organo-substituted derivative of phosphorous acid, and if required or desired, subjecting the resulting compound, prior to or subsequent to isolation and any separation into its stereochemical isomers, if a mixture of isomers of compounds of formula (III) was subjectedr USAB- USRE32465 E Aza penem cpds. of formula (II) and salts are new. In (II), R1 is lower alkyl R8-C(O)-amino, where R8 is lower alkyl opt. substd. one or more mono- or bi-carbocyclic aromatics alkoxy, PhO, 2-6C alkenyl or -alkynyl,4-6Ccycloalkyl, heteroaryl opt. substd. R4 is H, lower alkyl or Ph opt. substd. Py, furanyl, thienyl; R5 is H or O-protecting gp; R2 is lower alkyl substd. Ph R3 is nitrile, tetrazole -COOR6 where R6 is lower alkyl or alkyltrihalogenmethyl substd. Ph; Z is S, O, NR7; R7 is H, lower alkyl, substd. Ph, R8-C(O)- or N-protecting gp. - (II) are prepd. by new process comprising reacting appropriate 4-substd.-azetidine-2-one (A) with acid halide (B) in presence of tert.amine and alkaline earth metal carbonate to prod. 1-imido-4-substd.-azetidine-2-one (C), which is reacted with trialkyl phosphite to (II).